**2.2 Technical support**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

therapeutic alternative.

persons with T2D. [6]

and guidelines. [23–25]

**2.1 Therapeutic education**

pumps in daily routine of diabetes care.

The discovery of insulin by Paulesco in 1921 [4] and its final introduction to human medicine by Banting, Collip, Best and Macleod in 1922 [5] saved many lives of people with T1D. However, in T2D insulin was mostly used as an ultimate

In 1957, the discovery of metformin resulted in reduction of hyperglycaemia without hypoglycaemias. In the course of several decades, metformin proved to be a relatively effective mean to reduce body mass and cardiovascular complications. In addition, in persons on metformin the frequency of neoplasms appears to be lower. Today, metformin undoubtedly remains the drug worthy of choice for the majority

At the end of the 20th century, a new concept of pathophysiologic approach to T2D was suggested by Bruns [7] under the descriptive term "complementary therapy", and, independently by Berger [8, 9] as "supplementary therapy".

Important role in the intensification of insulin regimens played insulin pens which were produced since the year 1983. [10] At the beginning of the 21st century, insulin pumps (first implemented by John Pickup in 1978 [11]) and intensive selfmonitoring were also applied in people with T2D. [12–14] Despite of pumps many persons with T2D were unable to reach the expected metabolic improvement until

In 1974, the first glucometer (Ames) was introduced into clinical practice, followed by tenths of other glucometers [17–19], Continuous Glucose Monitors (CGM) [20] and/or Flash Glucose Monitors (FGM) [21]. Today, these devices have become mandatory means (together with HbA1c analysers [22]) to assess the metabolic control. Scientific inventions from the last 100 years were applied in official statements

This overview introduces promoting insights and better understanding of pathophysiologic approach to various treatments of T2D. Purpose of the presented case reports and single-centre "real world trials "is to motivate to education and to implementation of incretins and/or gliflozins and/or insulin analogs and/or insulin

**2. Prerequisites for a pathophysiologic approach to T2D management**

however, most of them remained unnoticed in everyday practice.

Lifestyle and education of people with chronic disorders have been recognised as an essential part of treatment. Many anonymous dedicated enthusiasts have created a solid platform for effective therapy. Some of them became famous educators,

The Diabetes Education Study Group (DESG) of the European Association for the Study of Diabetes (EASD), was founded in 1977 [26] and the Therapeutic Patient Education (TPE) became a goal of many respected bodies in the world.

The DESG aimed to improve the quality of life through educational programmes designed to foster independence for the patient, to improve the quality of metabolic control, to emphasise the prevention and to encourage research. The DESG organised activities all over the Europe, published more than 30 Teaching letters and Series of the 5-min education basics. In eastern countries, the DESG workshops (Bucharest, 1982, Balatonfuered, 1985, Warsaw, 1987, Weimar, 1989, Olomouc, 1991) supported the cooperation between health care providers (physicians, teachers, psychologists, nurses, dietitians, social workers) and patients. (**Figure 1**) Therefore, the adopted 5- day scheduled teaching programs created by Assal, Berger and Jörgens in Genf and Düsseldorf [27] could be spread throughout Europe. Workshops at Grimentz,

incretin receptor agonists and gliflozins have been made available. [15, 16]

**4**

#### *2.2.1 Development and clinical implementation of insulin pens*

Insulin pens opened the door to comfortable insulin administration thereby making the intensive regimens acceptable at work, at school, at leisure, during travels, etc.

In 1983, the first models of a MAnual Device for Insulin (MADI) proved to be a useful aid to injection of U-40 insulin either as a needle pen or as a catheter pen. [10] Within a few years other injectors appeared. [30, 31] Six models of a new type of MADI for insulin U-40, U-80 and U-100 were developed. [32] (**Figure 2**) In the needle pen (**Figure 3**) a sliding cover prevents the contamination of the needle which remains invisible in the course of injection and might be reused without sterilization. [33] In the catheter pen (**Figure 4**) the catheter remained inserted in subcutaneous tissue for 3 days. A syringe-like interchangeable plastic reservoir (3 ml) was refilled from insulin vials with any kind of soluble insulin. Actual insulin administration occurred by twisting the cap after subcutaneous insertion of needle or catheter.

To date, about one hundred of various types of insulin or incretin needle-pens have been distributed all over the world. (**Figure 5**) Most of them are disposable

pens [34] (prefilled with insulin, to be discarded after emptying), some of them are constructed for cartridged insulin produced by the respective company.

Despite initial enthusiasm, the preference of catheter pens [35] (**Figure 6**) was low over time.

#### **Figure 2.**

*Scheme of MADI: needle pen with telescopic sliding cover (left) and catheter pen [32] (1991).*

**7**

**Figure 4.**

**Figure 5.**

*MADI – catheter pen [35] (1994).*

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020*

*2.2.2 Trials for testing accuracy and precision of glucometer-strips systems*

*Heaps of insulin or incretin pens produced by different companies all over the world since 1983.* 

of our therapeutic recommendations.

*Photo V. Kupčik, Diabetes Museum, Háj ve Slezsku, CR. (2019).*

Within the course of 25 years, we have tested the accuracy and precision of glucometer-strips systems Card (Medisense), OPTIUM (Abbott), ADVANCE (Hypoguard, GB) [17] and LINUS (Agamatrix, USA). [18] to support the reliability

The purpose of our last experimental and clinical trial (2010–2013) [19] was (1) to assess the electrochemistry-based glucometers CONTOURLINK (Bayer, Germany) using glucose dehydrogenase strips, CALLA, (Wellion, Austria) and

*DOI: http://dx.doi.org/10.5772/intechopen.96237*

**Figure 3.** *MADI – needle pen in the course of injection (1994).*

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020 DOI: http://dx.doi.org/10.5772/intechopen.96237*

**Figure 4.** *MADI – catheter pen [35] (1994).*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

low over time.

**Figure 2.**

pens [34] (prefilled with insulin, to be discarded after emptying), some of them are

Despite initial enthusiasm, the preference of catheter pens [35] (**Figure 6**) was

constructed for cartridged insulin produced by the respective company.

*Scheme of MADI: needle pen with telescopic sliding cover (left) and catheter pen [32] (1991).*

**6**

**Figure 3.**

*MADI – needle pen in the course of injection (1994).*

**Figure 5.**

*Heaps of insulin or incretin pens produced by different companies all over the world since 1983. Photo V. Kupčik, Diabetes Museum, Háj ve Slezsku, CR. (2019).*

#### *2.2.2 Trials for testing accuracy and precision of glucometer-strips systems*

Within the course of 25 years, we have tested the accuracy and precision of glucometer-strips systems Card (Medisense), OPTIUM (Abbott), ADVANCE (Hypoguard, GB) [17] and LINUS (Agamatrix, USA). [18] to support the reliability of our therapeutic recommendations.

The purpose of our last experimental and clinical trial (2010–2013) [19] was (1) to assess the electrochemistry-based glucometers CONTOURLINK (Bayer, Germany) using glucose dehydrogenase strips, CALLA, (Wellion, Austria) and

**Figure 6.** *Various catheter pens: MADI (CR), MD2 (GDR), D pen (CH) (1989).*

**Figure 7.**

*Correlations (Spearman) between PG estimations on INTEGRA vs. CALLA [19] (2013).*

LINUS (Agamatrix, USA) both using glucose oxidase strips; (2) to evaluate diabetes control using Ambulatory Glycaemic Profiles (AGP) and comparing the results with those of the COBAS INTEGRA 400 Plus analyser. There were 112 sets (each from one person) analysed. Means of 3 PG estimations on glucometers and on INTEGRA analyser were calculated.

Strong correlations between PG values estimated on COBAS INTEGRA analyser vs. individual glucometers (CONTOURLINK, CALLA, LINUS) were shown (**Figure 7**).

**9**

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020*

Deviations from INTEGRA were within the range ± 15%. (**Figure 8**) PG variability was measured by SD: SD INTEGRA = 0.061 mmol/l, SD CONTOURLINK = 0.256 mmol/l, SD CALLA = 0.290 mmol/l, SD LINUS = 0.286 mmol/l. The mean INTEGRA PG

*Relative deviations of glucometer estimations from estimations on analyser Cobas Integra. PG deviations of respective glucometers from INTEGRA PG were within the range ± 15% (i.e. in 94.6%, 93.8%, 97.3% of 112* 

All persons with T2D performed 10-point PG profiles to optimise balance between meals, physical exercise, and insulin boluses. PG differences between the respective glucometer-strips system and COBAS INTEGRA laboratory values were in borderline of ISO 15197. [25]. So, the practical acceptability of all tested glucometer-strips systems was demonstrated. Nevertheless, due to different (even though acceptable) accuracy of individual systems, it is advisable to use one type of glucometer-strips system in each diabetes centre. Since 2013 all our patients are trained in SMPG on glucometer CALLA. If insulin pump MINIMED 640 G is used, glucometer

CONTOUR PLUS is sometimes preferred due to wireless signal transmission.

In 2005–2013 we tested benefits of CGM in three independent studies. Two of them were performed in people with T2D and T1D treated by insulin pumps PARADIGM (Medtronic MiniMed, Nordthridge, CA, USA). One study aimed to

The pump PARADIGM 722 communicates with CGM and enables daily reading of 288 PG values determined by a SENsor inserted into subcutaneous tissue (PARASEN study). Real-time PG values are helpful to adapt further treatment.

Aim of this clinical study [36] was to compare the evolution of HbA1c over the 3- month period with CGM vs. a period with conventional SMPG by glucometers. Two cohorts of T1D + T2D on insulin pumps PARADIGM were investigated. Cohort 1 comprised 17 persons using CGM sensors for continuous glucose monitoring (CGM group). Cohort 2 comprised 25 people performing self-monitoring as before (3 to 6 times/d) on glucometer LINUS, Wellion, Agamatrix (SMPG group).

*2.2.3 Trials for the efficiency of continuous glucose monitoring (CGM)*

*2.2.3.1 Single center trial for benefits of CGM vs SMPG (2005–2009)*

patients without insulin pump in perioperative care.

*DOI: http://dx.doi.org/10.5772/intechopen.96237*

values ranged from 2.7 to 25.3 mmol/l.

**Figure 8.**

*pairs, resp.) [19] (2013).*

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020 DOI: http://dx.doi.org/10.5772/intechopen.96237*

#### **Figure 8.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

*Various catheter pens: MADI (CR), MD2 (GDR), D pen (CH) (1989).*

LINUS (Agamatrix, USA) both using glucose oxidase strips; (2) to evaluate diabetes control using Ambulatory Glycaemic Profiles (AGP) and comparing the results with those of the COBAS INTEGRA 400 Plus analyser. There were 112 sets (each from one person) analysed. Means of 3 PG estimations on glucometers and on INTEGRA

*Correlations (Spearman) between PG estimations on INTEGRA vs. CALLA [19] (2013).*

Strong correlations between PG values estimated on COBAS INTEGRA analyser vs. individual glucometers (CONTOURLINK, CALLA, LINUS) were shown (**Figure 7**).

**8**

**Figure 7.**

**Figure 6.**

analyser were calculated.

*Relative deviations of glucometer estimations from estimations on analyser Cobas Integra. PG deviations of respective glucometers from INTEGRA PG were within the range ± 15% (i.e. in 94.6%, 93.8%, 97.3% of 112 pairs, resp.) [19] (2013).*

Deviations from INTEGRA were within the range ± 15%. (**Figure 8**) PG variability was measured by SD: SD INTEGRA = 0.061 mmol/l, SD CONTOURLINK = 0.256 mmol/l, SD CALLA = 0.290 mmol/l, SD LINUS = 0.286 mmol/l. The mean INTEGRA PG values ranged from 2.7 to 25.3 mmol/l.

All persons with T2D performed 10-point PG profiles to optimise balance between meals, physical exercise, and insulin boluses. PG differences between the respective glucometer-strips system and COBAS INTEGRA laboratory values were in borderline of ISO 15197. [25]. So, the practical acceptability of all tested glucometer-strips systems was demonstrated. Nevertheless, due to different (even though acceptable) accuracy of individual systems, it is advisable to use one type of glucometer-strips system in each diabetes centre. Since 2013 all our patients are trained in SMPG on glucometer CALLA. If insulin pump MINIMED 640 G is used, glucometer CONTOUR PLUS is sometimes preferred due to wireless signal transmission.

#### *2.2.3 Trials for the efficiency of continuous glucose monitoring (CGM)*

In 2005–2013 we tested benefits of CGM in three independent studies. Two of them were performed in people with T2D and T1D treated by insulin pumps PARADIGM (Medtronic MiniMed, Nordthridge, CA, USA). One study aimed to patients without insulin pump in perioperative care.

The pump PARADIGM 722 communicates with CGM and enables daily reading of 288 PG values determined by a SENsor inserted into subcutaneous tissue (PARASEN study). Real-time PG values are helpful to adapt further treatment.

#### *2.2.3.1 Single center trial for benefits of CGM vs SMPG (2005–2009)*

Aim of this clinical study [36] was to compare the evolution of HbA1c over the 3- month period with CGM vs. a period with conventional SMPG by glucometers.

Two cohorts of T1D + T2D on insulin pumps PARADIGM were investigated. Cohort 1 comprised 17 persons using CGM sensors for continuous glucose monitoring (CGM group). Cohort 2 comprised 25 people performing self-monitoring as before (3 to 6 times/d) on glucometer LINUS, Wellion, Agamatrix (SMPG group).

#### **Figure 9.**

*Benefits of CGM in individuals on insulin pump [36] (2013).*

In the CGM group (but not in the SMPG group) HbA1c significantly dropped within one month and remained reduced as long as the CGM was applied, i.e., until the switch back to SMPG. (**Figure 9**).

Hence, continuous glucose monitoring with transcutaneous sensors appeared to be an important measure for improving metabolic compensation in people with diabetes. With CGM, the evolution of HbA1c showed metabolic improvement. The PARASEN study demonstrated that continuous self-monitoring should become a regular part of treatment in educated persons on insulin pumps.

Several years later, the COMISAIR study [37] demonstrated that also a conventional intensive multiple dose insulin regimen (MDI), if supported by CGM, can be a suitable alternative to CGM augmented insulin pump therapy.

#### *2.2.3.2 Multicenter trial on CGM-augmented insulin pump therapy in T1D (2005–2009)*

The multicenter CGM study (2005–2009) [38] aimed to the assessment of benefits of CGM-augmented insulin pump therapy for persons with T1D.

Community or academic practices in six Central and Eastern European/ Mediterranean countries established a registry of people with T1D starting CGMaugmented insulin pump therapy with the pump PARADIGM® X22 under everyday conditions. We compared HbA1c values before and after 3 months of CGM and assessed relationships between insulin therapy and glycaemia-related variables.

Sensor data and HbA1c data were evaluated in 85 of 102 enrolled persons with longstanding T1D, mean age 33.2 ± 16.9 years. Mean HbA1c declined after 3 months of CGM from 59.0 ± 8.9 mmol/mol at baseline to 50.9 ± 11.7 mmol/mol (P < 0.001).

Hence, CGM-augmented insulin pump therapy appeared to improve glycaemic control in T1D in everyday practice settings.

#### *2.2.3.3 The trial for CGM benefits in perioperative care (2009–2013)*

Our third CGM study (2009–2013) [39] payed attention to the assessment of implementation of CGM in perioperative care of T2D.

**11**

**Figure 10.**

*hyperinsulinaemia remains over 3 h) [7] (1995).*

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020*

PG monitoring was performed by means of GUARDIAN REAL-Time CGMS (Medtronic, Northridge, USA) in perioperative periods of 20 persons with T2D.

This approach was successful in the intensive care unit setting only. Neither electromagnetic interference nor other side effects appeared. No significant difference between sensor and laboratory analyser values was found. Pearson's correlation coefficients between PG by sensor and by Wellion Linus glucometer during the whole perioperative period were significantly strong (0.9). Hypoglycaemia was

So, transcutaneous CGM appears to be a safe approach offering a detailed insight

Disturbed dynamics of insulin secretion in T2D (**Figure 10**) makes the need of

We concluded that in T2D better metabolic control can be achieved with complementary insulin therapy than with oral antidiabetic drugs or long-acting insulin 1–2 times daily. Our "surprising" results were based on pathophysiologic concept of Bruns, Berger and Kalfhaus. [7–9] To date, intensive insulin therapy in people with

*Dynamics of insulin secretion in blood in healthy people (initial postprandial peak is present, insulin concentration returns to baseline within 3 h); in T2D (missing Initial peak, maximum is delayed and* 

into perioperative PG homeostasis. However, confirmation of sensor data by an

**3. Clinical trials on effectiveness of preprandial complementary** 

small complementary preprandial boluses of rapid insulin understandable. In the years 1991–2019 we carried out three single centre trials to this topic.

In 1991–1994, a nonrandomized uncontrolled study with 251 T2D assessed the effectiveness of supplementary insulin regimen [40, 41] The complementary insulin therapy using insulin pen MADI started in hospital following the baseline PG profile on day 2. The final ten-point PG profile was performed on day 4. (**Figures 11** and **12**) At a check-up 8–10 weeks later a decrease of HbA1c, BMI and improved lipoprotein-spectrum was found

Sensor was inserted on the day before surgery and continued for 3 days.

*DOI: http://dx.doi.org/10.5772/intechopen.96237*

registered in 4 of 20 persons.

approved method remains necessary.

**3.1 Trial on effectiveness of rapid insulin**

(**Figures 13** and **14**).

**(= supplementary) insulin boluses in T2D**

T2D appears to be more accepted in daily routine. [6, 23]

*Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020 DOI: http://dx.doi.org/10.5772/intechopen.96237*

PG monitoring was performed by means of GUARDIAN REAL-Time CGMS (Medtronic, Northridge, USA) in perioperative periods of 20 persons with T2D. Sensor was inserted on the day before surgery and continued for 3 days.

This approach was successful in the intensive care unit setting only. Neither electromagnetic interference nor other side effects appeared. No significant difference between sensor and laboratory analyser values was found. Pearson's correlation coefficients between PG by sensor and by Wellion Linus glucometer during the whole perioperative period were significantly strong (0.9). Hypoglycaemia was registered in 4 of 20 persons.

So, transcutaneous CGM appears to be a safe approach offering a detailed insight into perioperative PG homeostasis. However, confirmation of sensor data by an approved method remains necessary.
